Histamine exhibits bronchial smooth muscle constricting action and capillaropenetration accelerating action as a result of its binding to the H.sub.1 receptor in cell membranes, and is considered to be an important mediator in allergic diseases. Described specifically, histamine is believed to cause aggravation of asthmatic symptoms by its bronchoconstricting action and also to increase transudation of blood components into intercellular spacings due to accelerated capillaropenetration and hence to take part in the formation of edema seen in allergic rhinitis and conjunctivitis. For the treatment of these allergic diseases, antihistaminic agents are therefore used. Conventional antihistaminic agents however bind to the H.sub.1 receptor in the brain, so that side effects on the central nerve system, such as drowsiness, are concerned. In recent years, bronchial asthma is regarded as eosinophilic chronic inflammation of the airway, and a late asthmatic response that the symptom of airway constriction which is typical to asthma is developed due to infiltration of inflammatory cells on the bronchial mucosa, oversecretion of mucus and the like is at issue. Antihistaminic agents are not effective for such late asthmatic responses, leading to the existence of an outstanding desire for the development of pharmaceuticals of a new type for their treatment.
Leukotrienes (LT) are associated with causes for most inflammatory diseases, especially asthma, psoriasis, rheumatism and inflammatory colitis, and are considered to play an important role in inflammatory processes through cytopathy. Leukotrienes are principal mediators of allergy and inflammation, and therefore many substances which inhibit the action and/or syntheses of leukotrienes are being discovered for the treatment of these diseases (S. T. Holgate et al.: J. Allergy Clin. Immunol., 98, 1-13, 1996).
Leukotrienes are arachidonate metabolites synthesized by 5-lipoxygenase (5-LO), and consist of two groups. One of the groups is LTB.sub.4 and has strong chemotaxis towards leukocytes. The other group is collectively called cysteine leukotrienes (CySLT) and includes LTC.sub.4, LTD.sub.4 and LTE.sub.4. As biologically active substances, they have been called "slow-reacting substances of anaphylaxis (SRS-A)" for many years. CysLT binds to their receptors in human tissues to exert its action. A selective LTD.sub.4 receptor inhibitor has been found to inhibit contracting actions of both LTC.sub.4 and LTD.sub.4 in human lung tissues, so that LTC.sub.4 is suggested to bind to the same site of a receptor as LTD.sub.4 (Buckner C. K. et al: Ann. NY Acad. Sci., 524, 181-6, 1988; Aharony D. et al.: New Trends in Lipid Mediators Research, Basel: Karger 67-71, 1989). LTE.sub.4 is also considered to act via the same receptor as LTD.sub.4, but is called a partially active substance for its lower potency.
Described specifically, in an allergic disease such as asthma, an immediate asthmatic response such as bronchial constriction and edematous formation, in which histamine or the like takes principal part, and a late asthmatic response such as airway constriction due to cell infiltration, mucus secretion or mucosal hypertrophy, in which a leukotriene or the like takes part are considered to be important for the development of morbid conditions. In allergic rhinitis, there is similarly a move toward taking each morbid condition as a biphasic response that histamine takes a profound part in an immediate response such as sternutation or nasal oversecretion and leukotriene takes an important part in a late response such as a rhinostenostic symptom due to edema of the nasal mucosa.
A compound having antagonism against both a histamine H.sub.1 receptor and an LTD.sub.4 receptor and less tendency of brain penetration is therefore considered to prevent or cure a variety of allergic diseases, especially a series of symptoms of asthma or rhinitis, which ranges from an immediate response to a late response, and to become an effective pharmaceutical of reduced side effects.
It is however the current circumstances that no compound has been found with fully satisfactory antagonism against both an LTD.sub.4 receptor and a histamine H.sub.1 receptor. Further, many of LTD.sub.4 antagonists which have been developed so far contain at least one acidic group, so that these LTD.sub.4 antagonists are hydrophilic compounds having high polarity. They are thus unavoidably insufficient in absorption upon inhalative administration or oral administration. This is believed to have led to the increased doses of these pharmaceuticals and hence, to the development of side effects.
Therefore, an object of the present invention is to provide a compound making combined use of both antileukotrienic action and antihistaminic action, having low tendency of brain penetration and containing no acidic group in its molecule; and also a medicine comprising this compound as an effective ingredient.